Homology modeling and docking studies of a Δ9-fatty acid desaturase from a Cold-tolerant Pseudomonas sp. AMS8.
Membrane-bound fatty acid desaturases perform oxygenated desaturation reactions to insert double bonds within fatty acyl chains in regioselective and stereoselective manners. The Δ9-fatty acid desaturase strictly creates the first double bond between C9 and 10 positions of most saturated substrates. As the three-dimensional structures of the bacterial membrane fatty acid desaturases are not available, relevant information about the enzymes are derived from their amino acid sequences, site-directed mutagenesis and domain swapping in similar membrane-bound desaturases. The cold-tolerant Pseudomonas sp. AMS8 was found to produce high amount of monounsaturated fatty acids at low temperature. Subsequently, an active Δ9-fatty acid desaturase was isolated and functionally expressed in Escherichia coli. In this paper we report homology modeling and docking studies of a Δ9-fatty acid desaturase from a Cold-tolerant Pseudomonas sp. AMS8 for the first time to the best of our knowledge. Three dimensional structure of the enzyme was built using MODELLER version 9.18 using a suitable template. The protein model contained the three conserved-histidine residues typical for all membrane-bound desaturase catalytic activity. The structure was subjected to energy minimization and checked for correctness using Ramachandran plots and ERRAT, which showed a good quality model of 91.6 and 65.0%, respectively. The protein model was used to preform MD simulation and docking of palmitic acid using CHARMM36 force field in GROMACS Version 5 and Autodock tool Version 4.2, respectively. The docking simulation with the lowest binding energy, -6.8 kcal/mol had a number of residues in close contact with the docked palmitic acid namely, Ile26, Tyr95, Val179, Gly180, Pro64, Glu203, His34, His206, His71, Arg182, Thr85, Lys98 and His177. Interestingly, among the binding residues are His34, His71 and His206 from the first, second, and third conserved histidine motif, respectively, which constitute the active site of the enzyme. The results obtained are in compliance with the in vivo activity of the Δ9-fatty acid desaturase on the membrane phospholipids.


Best Practice Framework of Fracture Liaison Services in Spain and their coordination with Primary Care.
The coordination of Fracture Liaison Services (FLS) with Primary Care (PC) is necessary for the continuity of care of patients with fragility fractures. This study proposes a Best Practice Framework (BPF) and performance indicators for the implementation and follow-up of FLS-PC coordination in clinical practice in Spain. To develop a BPF for the coordination of FLS with PC in Spain and to improve the continuity of care for patients with fragility fractures. A Steering Committee selected experts from seven Spanish FLS and related PC doctors and nurses to participate in a best practice workshop. Selection criteria were an active FLS with an identified champion and prior contact with PC centres linked to the hospital. The main aim of the workshop was to review current FLS practices in Spain and their integration with PC. A BPF document with processes, tools, roles, and metrics was then generated. Spanish FLS consists of a multidisciplinary team of physicians/nurses but with low participation of other professionals and PC staff. Evaluation and treatment strategies are widely variable. Four desired standards were agreed upon: (1) Effective channels for FLS-PC communication; (2) minimum contents of an FLS clinical report and its delivery to PC; (3) adherence monitoring 3 months after FLS baseline visit; and (4) follow-up by PC. Proposed key performance indicators are (a) number of FLS-PC communications, including consensus protocols; (b) confirmation FLS report received by PC; (c) medical/nursing PC appointment after FLS report received; and (d) number of training sessions in PC. The BPF provides a comprehensive approach for FLS-PC coordination in Spain, to promote the continuity of care in patients with fragility fractures and improve secondary prevention. The implementation of BPF recommendations and performance indicator tracking will benchmark best FLS practices in the future.


A mixed-methods study of maternal near miss and death after emergency cesarean delivery at a referral hospital in Somaliland.
To explore maternal near miss and death after emergency cesarean delivery in Somaliland, including the impact of the prerequisite for family consent. A facility-based, mixed-methods study was conducted to assess all maternal near misses and deaths recorded at a referral hospital that provided services to women from all regions of Somaliland. The data sources comprised a quantitative prospective cross-sectional study using the WHO near-miss tool (performed from August 1 to December 31, 2015) and qualitative interviews with 17 healthcare providers working at the referral hospital who were in direct contact with the women in labor (performed from January 15 to March 15, 2015). Of the 138 maternal near misses and deaths recorded, 50 (36%) were associated with emergency cesarean delivery. The most frequent maternal complication was severe pre-eclampsia (n=17; 34%), and the most frequent underlying causes were hypertensive disorders (n=31; 62%) and obstetric hemorrhage (n=15; 30%). Healthcare providers were often prevented from performing emergency cesarean delivery until the required consent had been received from the woman's extended family. Maternity care in Somaliland must be improved, and the issue of legal authority for consent examined, to ensure both safe and timely provision of emergency cesarean delivery.


Association of EDARV370A with breast density and metabolic syndrome in Latinos.
The ectodysplasin receptor (EDAR) is a tumor necrosis factor receptor (TNF) superfamily member. A substitution in an exon of EDAR at position 370 (EDARV370A) creates a gain of function mutant present at high frequencies in Asian and Indigenous American populations but absent in others. Its frequency is intermediate in populations of Mexican ancestry. EDAR regulates the development of ectodermal tissues, including mammary ducts. Obesity and type 2 diabetes mellitus are prevalent in people with Indigenous and Latino ancestry. Latino patients also have altered prevalence and presentation of breast cancer. It is unknown whether EDARV370A might connect these phenomena. The goals of this study were to determine 1) whether EDARV370A is associated with metabolic phenotypes and 2) if there is altered breast anatomy in women carrying EDARV370A. Participants were from two Latino cohorts, the Arizona Insulin Resistance (AIR) registry and Sangre por Salud (SPS) biobank. The frequency of EDARV370A was 47% in the Latino cohorts. In the AIR registry, carriers of EDARV370A (GG homozygous) had significantly (p < 0.05) higher plasma triglycerides, VLDL, ALT, 2-hour post-challenge glucose, and a higher prevalence of prediabetes/diabetes. In a subset of the AIR registry, serum levels of ectodysplasin A2 (EDA-A2) also were associated with HbA1c and prediabetes (p < 0.05). For the SPS biobank, participants that were carriers of EDARV370A had lower breast density and higher HbA1c (both p < 0.05). The significant associations with measures of glycemia remained when the cohorts were combined. We conclude that EDARV370A is associated with characteristics of the metabolic syndrome and breast density in Latinos.


Different temporal behavior for the forward- and backward-circulating radiation within a microdroplet.
Spatially resolved nonlinear scattering of a train of picosecond pulses from ethanol microdroplets is investigated. Different time behavior is observed for light with the same and the opposite sense of circulation as the input-coupled light. The forward-circulating light exhibits a smooth, delayed pulse-to-pulse growth, attributed to increased input coupling with time induced by the laser pulses. The backward-circulating light has an irregular time behavior, attributed to near-backward stimulated Brillouin scattering. Increased scattering as a result of CO(2) (compared with He) dissolved gas is demonstrated by an intensity decrease of the spatially precessed radiation on a cavity resonance.


Promoting equity in the mental wellbeing of children and young people: a scoping review.
There is increasing emphasis on wellbeing as a target for mental health promotion, especially during the formative period of childhood. Despite growing research on the importance of mental wellbeing, there is little information on how to effectively promote it or how to promote it equitably. This article presents a scoping review of interventions which seek to promote mental wellbeing and reduce inequities in children and young people living in high income countries. We used Fair Foundations: The VicHealth framework for health equity (VicHealth (2013) Melbourne, Australia: The Victorian Health Promotion Foundation) to identify points of entry at three layers of influence: (i) socioeconomic, cultural and political contexts, (ii) daily living conditions, and (iii) individual and family health-related factors. We identified more than 1000 interventions which aimed to prevent or treat childhood mental illness, but there were far fewer that aimed to promote children's or young people's mental wellbeing. The interventions we studied were either universal or specifically targeted children from disadvantaged families: none explicitly used an equity framework to guide their design or evaluation or addressed social gradients in wellbeing. Most interventions remained focused on proximate factors, although we also identified a handful of interventions that sought to address children's access to services and their educational and neighbourhood environments. However, we found encouraging evidence that interventions in family and educational settings were successful in building children's strengths and supporting positive parenting, universally and within disadvantaged groups. Such positive programme evaluations signal the potential for using a proportionate universalism approach that emphasizes equity in the promotion of mental wellbeing.


The physiology of altered eating behaviour after Roux-en-Y gastric bypass.
Obesity and its related comorbidities can be detrimental for the affected individual, as well as constituting a major challenge to public health systems worldwide. Currently, the most effective treatment option leading to clinically significant and maintained body weight loss and reduction in obesity-related morbidity and mortality is obesity surgery, which is recommended for patients with a body mass index of >40 kg m(-2), or >35 kg m(-2) if obesity-associated comorbidities, such as type 2 diabetes mellitus, are present. This report focuses on the altered eating behaviour after the most common of these operations, the Roux-en-Y gastric bypass. Animal and human experiments designed to understand the underlying physiological mechanisms of altered taste and appetite are discussed.


Bonding to enamel and dentin using self-etching adhesive systems.
This study investigated the effectiveness of three different dentin adhesive systems on the adhesion of resin composite to both dentin and enamel. The flat dentin and enamel surfaces of 60 extracted human molar teeth were exposed by wet grinding with 600-grit silicon carbide paper. One total-etch self-priming adhesive system (Prime & Bond NT), one two-step self-etching primer adhesive system (Clearfil SE Bond), and one "all-in-one" self-etching adhesive system (Prompt L-Pop) were evaluated. Each bonding system was applied according to the manufacturer's instructions and followed by composite (TPH Spectrum) application. Twenty-four hours after bonding, the teeth were subjected to shear testing. There were 10 replicates for each group. Prompt L-Pop exhibited significantly higher bond strength values to enamel (27 +/- 4.2 MPa) than all other groups. There were no statistically significant differences for shear bond strength to dentin among adhesives. Prompt L-Pop showed the statistically significantly higher bond strength to enamel than dentin. There were no statistically significant differences between the enamel and dentin bond strengths of Clearfil SE Bond and Prime & Bond NT. The self-etching adhesive systems produced high bond strengths to human coronal dentin and ground enamel surfaces. These materials seem to be very promising for further clinical applications, and the results are very encouraging for the clinical success of these simplified adhesive systems. The self-etching adhesive systems produced even better bond strengths to both enamel and dentin than conventional total-etch systems, especially the "all-in-one" system, which produced the highest bond strength to enamel.


Partially defatted olive cake in finishing pig diets: implications on performance, faecal microbiota, carcass quality, slurry composition and gas emission.
One of the key factors to improve swine production sustainability is the use of agro-industrial by-products in feeds, such as olive by-products. However, it is necessary to assess its effects on the overall production process, including the animal and the environment. With this aim, an experiment was conducted to determine the effects of including a partially defatted olive cake (PDOC) in pig diets on growth performance, faecal microbiota, carcass quality and gas emission from the slurry. Two finishing diets were formulated, a control (C) diet and a diet with PDOC included at 120 g/kg. Eighty finishing male pigs Duroc-Danbred × (Landrace × Large White) of 60.4 ± 7.00 kg BW were divided between these two treatments. During the finishing period (60 to 110 kg BW, 55 days) average daily gain, average daily feed intake and feed conversion ratio were recorded. Faecal samples from the rectum of 16 animals per treatment were incubated for bacteria enumeration. At the end of finishing period, backfat thickness and loin depth (LD) were measured. Animals were slaughtered to obtain carcass weight and carcass composition parameters, and subcutaneous fat was sampled to analyse the fatty acid (FA) profile. In addition greenhouse gas and ammonia emissions were measured during pig slurry storage using the methodology of dynamic flux chambers. An initial slurry characterisation and biochemical methane potential (B0) were also determined. No significant differences between treatments were found in performance, carcass quality and microbial counts with the exception of LD, which was lower in PDOC compared with C animals (45.5 v. 47.5 mm, SEM: 0.62; P = 0.020). The FA profile of the subcutaneous fat did not differ between treatments, but the monounsaturated FA (MUFA) concentration was higher and the polyunsaturated FA was lower in the animals fed PDOC (50.9 v. 48.3, SEM: 0.48, P < 0.001; 17.6 v. 19.3, SEM: 0.30, P < 0.001 in mg/100 g of Total FA, for PDOC and C animals, respectively). The initial pig slurry characterisation only showed differences in ADF concentration that was higher (P < 0.05) in the slurry from PDOC treatment. Regarding gas emission, slurries from both treatments emitted similar amounts of ammonia (NH3), carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O), as well as B0 values. The results obtained suggest that PDOC may be included in balanced pig diets at rates of up to 120 g/kg without negative effects on performance, carcass quality, gut microflora and slurry gas emission, while improving the MUFA concentration of subcutaneous fat.


Changes in water-holding capacity and textural properties of chicken gizzard stored at 4 degrees C.
The water-holding capacity (WHC), and toughness (shear force) of chicken gizzard were evaluated during postmortem storage for 4.5, 7, 12, 24, 48, 72 and 96 h at 4 degrees C. Degradation of the cytoskeletal proteins desmin, talin and vinculin were monitored by sodium dodecyl sulfate--polyacrylamide gel electrophoresis and Western blotting during the same designated storage period. The WHC of the gizzards decreased significantly from 12 h to 72 h of storage, but by 96 h the WHC was restored to the level measured after storage for 12 h. The shear force value of the gizzards increased rapidly until 12 h and then decreased until 24 h, with a further slight decrease by 48 h. Degradation products of desmin, talin and vinculin appeared at 96 h, 12 h and 48 h postmortem, respectively. The intensity of immunolabeling for desmin, talin and vinculin after storage for 96 h decreased to 51%, 25% and 52% of the initial value. The appearance of desmin degradation products was accompanied by an increase in WHC. This suggests that the postmortem degradation of desmin is involved in the increase of WHC in chicken gizzard during storage at 4 degrees C, and talin and vinculin may be involved.


Cerebral effects of extended hyperventilation in unanesthetized goats.
Thirty-six adult, male unanesthetized goats were hyperventilated to a PaCO2 level of 16-18 mm Hg for 6 hours. Arterial and sagittal sinus blood and cerebrospinal fluid were analyzed for pH, blood gases, bicarbonate, lactate, and pyruvate before hyperventilation, during hyperventilation, and after the termination of hyperventilation. Total cerebral blood flow, regional brain blood flows, and cerebral metabolic rate for oxygen were calculated from the distribution of radioactive microspheres. Intracranial pressure was measured in either the right or left cerebral ventricle. With the initiation of hyperventilation, cerebral blood flow and cerebral metabolic rate for oxygen fell significantly (64 +/- 5 ml/100 g/min to 41 +/- 3; 4.6 +/- 0.3 ml O2/100 g/min to 3.6 +/- 0.2), but both returned to prehyperventilation values within 6 hours of hyperventilation. With termination of hyperventilation, cerebral blood flow and cerebral metabolic rate for oxygen increased significantly above control levels (64 +/- 5 vs. 105 +/- 9; 4.6 +/- 0.3 vs. 5.4 +/- 0.4). Intracranial pressure was unaffected by hyperventilation or its termination. Arterial and sagittal sinus blood and cerebrospinal fluid pH increased with hyperventilation but returned to control values by 6 hours. However, pH was still significantly elevated at 6 hours. Lactate and pyruvate followed a similar pattern except in the cerebrospinal fluid, where both increased throughout the course of hyperventilation. There were no significant differences in the lactate:pyruvate ratio. On termination of hyperventilation, pH of the arterial and sagittal sinus blood and cerebrospinal fluid fell below control levels. Bicarbonate values decreased in all fluid compartments and were still below control values 2 hours after the cessation of hyperventilation.(ABSTRACT TRUNCATED AT 250 WORDS)


Enzymatic release of antitumor ether lipids by specific phospholipase A2 activation of liposome-forming prodrugs.
An enzymatically activated liposome-based drug-delivery concept involving masked antitumor ether lipids (AELs) has been investigated. This concept takes advantage of the cytotoxic properties of AEL drugs as well as the membrane permeability enhancing properties of these molecules, which can lead to enhanced drug diffusion into cells. Three prodrugs of AELs (proAELs) have been synthesized and four liposome systems, consisting of these proAELs, were investigated for enzymatic degradation by secretory phospholipase A(2) (sPLA(2)), resulting in the release of AELs. The three synthesized proAELs were (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phosphocholine (1-O-DPPC), (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phosphoethanolamine poly(ethylene glycol)(350) (1-O-DPPE-PEG(350)), and 1-O-DPPE-PEG(2000) of which 1-O-DPPC was the main liposome component. All three phospholipids were synthesized from the versatile starting material (R)-O-benzyl glycidol. A phosphorylation method, employing methyl dichlorophosphate, was developed and applied in the synthesis of two analogues of (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phosphoethanolamine poly(ethylene glycol). Differential scanning calorimetry has been used to investigate the phase behavior of the lipid bilayers. A release study, employing calcein encapsulated in non-hydrolyzable 1,2-bis-O-octadecyl-sn-glycero-3-phosphocholine (D-O-SPC) liposomes, showed that proAELs, activated by sPLA(2), perturb membranes because of the detergent-like properties of the released hydrolysis products. A hemolysis investigation was conducted on human red blood cells, and the results demonstrate that proAEL liposomes display a very low hemotoxicity, which has been a major obstacle for using AELs in cancer therapy. The results suggest a possible way of combining a drug-delivery and prodrug concept in a single liposome system. Our investigation of the permeability-enhancing properties of the AEL molecules imply that by encapsulating conventional chemotherapeutic drugs, such as doxorubicin, in liposomes consisting of proAELs, an increased effect of the encapsulated drug might be achievable due to an enhanced transmembrane drug diffusion.


Asbestos-related diseases in automobile mechanics.
Automobile mechanics have been exposed to asbestos in the past, mainly due to the presence of chrysotile asbestos in brakes and clutches. Despite the large number of automobile mechanics, little is known about the non-malignant respiratory diseases observed in this population. The aim of this retrospective multicenter study was to analyse the frequency of pleural and parenchymal abnormalities on high-resolution computed tomography (HRCT) in a population of automobile mechanics. The study population consisted of 103 automobile mechanics with no other source of occupational exposure to asbestos, referred to three occupational health departments in the Paris area for systematic screening of asbestos-related diseases. All subjects were examined by HRCT and all images were reviewed separately by two independent readers; who in the case of disagreement discussed until they reached agreement. Multiple logistic regression models were constructed to investigate factors associated with pleural plaques. Pleural plaques were observed in five cases (4.9%) and interstitial abnormalities consistent with asbestosis were observed in one case. After adjustment for age, smoking status, and a history of non-asbestos-related respiratory diseases, multiple logistic regression models showed a significant association between the duration of exposure to asbestos and pleural plaques. The asbestos exposure experienced by automobile mechanics may lead to pleural plaques. The low prevalence of non-malignant asbestos-related diseases, using a very sensitive diagnostic tool, is in favor of a low cumulative exposure to asbestos in this population of workers.


Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms.
Pulmonary hypertension (PH) is a potentially life-threatening condition arising from a wide variety of pathophysiologic mechanisms. Effective treatment requires a systematic diagnostic approach to identify all reversible mechanisms. Many of these mechanisms are relevant to those afflicted with obesity. The unique mechanisms of PH in the obese include obstructive sleep apnea, obesity hypoventilation syndrome, anorexigen use, cardiomyopathy of obesity, and pulmonary thromboembolic disease. Novel mechanisms of PH in the obese include endothelial dysfunction and hyperuricemia. A wide range of effective therapies exist to mitigate the disability of PH in the obese.


Mitochondrial proteomic profiling reveals increased carbonic anhydrase II in aging and neurodegeneration.
Carbonic anhydrase inhibitors are used to treat glaucoma and cancers. Carbonic anhydrases perform a crucial role in the conversion of carbon dioxide and water into bicarbonate and protons. However, there is little information about carbonic anhydrase isoforms during the process of ageing. Mitochondrial dysfunction is implicit in ageing brain and muscle. We have interrogated isolated mitochondrial fractions from young adult and middle aged mouse brain and skeletal muscle. We find an increase of tissue specific carbonic anhydrases in mitochondria from middle-aged brain and skeletal muscle. Mitochondrial carbonic anhydrase II was measured in the Purkinje cell degeneration (pcd5J) mouse model. In pcd5J we find mitochondrial carbonic anhydrase II is also elevated in brain from young adults undergoing a process of neurodegeneration. We show C.elegans exposed to carbonic anhydrase II have a dose related shorter lifespan suggesting that high CAII levels are in themselves life limiting. We show for the first time that the mitochondrial content of brain and skeletal tissue are exposed to significantly higher levels of active carbonic anhydrases as early as in middle-age. Carbonic anhydrases associated with mitochondria could be targeted to specifically modulate age related impairments and disease.


[Digital morphometric and stereologic analysis of small intestinal mucosa in well-nourished and malnourished children with persistent diarrhea].
To test the hypothesis that the proximal small intestines of children with persistent diarrhea present morphometric and stereologic changes proportional to their nutritional status, using microscope images stored in a computer. Cross-sectional study with 65 pediatric patients, whose ages ranged from 4 months to 5 years, with persistent diarrhea for over 14 days. The nutritional assessment was performed according to the z-scores for weight/age (W/A), weight/height (W/H) and height/age (H/A) ratios, divided into: well-nourished = z > or =2SD and malnourished = z<2SD; well-nourished = z > or =2SD, nutritional risk = z<1SD and malnourished = z<-2SD; and continuously, in descending order, using the NCHS charts. After obtaining the computer images using the software Scion Image, villous height, crypt depth, mucosal thickness, total mucosal thickness, and villous/crypt ratio were measured in the fragments of the small intestinal mucosa, enlarged 100 times. When images were enlarged 500 times, enterocyte height, nuclear height and brush-border height were measured. Stereologic analysis was performed using cycloid arcs. For W/A, W/H and H/A z-scores, divided into two nutritional status categories, no statistically significant difference was observed in regard to villous height, crypt depth, mucosal thickness, total mucosal thickness and villous/crypt ratio. Enterocyte height presented the most significant difference between well-nourished and malnourished groups, for W/A and W/H ratios, with a 500x enlargement, although this difference was not statistically significant. When z-scores were subdivided into three nutritional status categories, a digital morphometric analysis showed a statistically significant difference for villous/crypt ratio between the well-nourished and slightly malnourished group and the well-nourished and mild to severe malnourished group (p=0.048). The villous/crypt ratio was higher among well-nourished children. Using the Spearman coefficient, the variables enterocyte height, height of enterocyte nucleus and brush-border height presented a clear association with the W/A ratio (r=0.25; p=0.038), W/H ratio (r=0.029; p=0.019). The height of the enterocyte and the brush-border height were associated with W/H ratio. The observed associations between nutritional status and the analyzed small intestinal mucosa variables showed a positive correlation with patients' weight. Although these associations were of a slight to moderate magnitude, we observed a tendency of enterocyte size reduction, as well as a reduction in the size of its nucleus and brush-border, as the level of malnutrition increases.


Diagnostic Performance of Cerebrospinal Fluid Neurofilament Light Chain and Soluble Amyloid-β Protein Precursor β in the Subcortical Small Vessel Type of Dementia.
The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers. We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer's disease (AD), and mixed dementia (combined AD and SSVD). This was a mono-center study of patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and controls (n = 96). The CSF biomarkers were measured using immunoassays, and their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated. Elevated neurofilament light chain (NFL) and decreased sAβPPβ independently separated SSVD from controls, and sAβPPβ also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAβPPβ discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834-0.972). Additionally, sAβPPβ combined with the core AD biomarkers (amyloid-β42, total tau, and phosphorylated tau181) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830-0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838-0.968). The high accuracy of NFL and sAβPPβ to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAβPPβ in combination with the core AD biomarkers.


The occurrence of a protein in the extracellular products of streptococci isolated from patients with acute glomerulonephritis.
The present report compares the extracellular proteins of streptococci by sodium dodecyl sulfate polyacrylamide electrophoresis. A marked variation in the streptococcal extracellualr proteins (SEP) of different strains was detected, even in strains of similar serotypes. It was possible, however, to identify a single protein band that occurred predominantly in the SEP of strains isolated from patients with acute poststreptococcal glomerulonephritis (APSGN). This protein was generally not produced by streptococci obtained from patients without this disease. It appears to be immunologically similar in the various serotypes of streptococci isolated from patients with APSGN and can be demonstrated by immunofluorescence techniques to be present in the glomeruli of these patients.


The person-based approach to enhancing the acceptability and feasibility of interventions.
This paper provides three illustrations of how the "person-based approach" can be used to assess and enhance the acceptability and feasibility of an intervention during the early stages of development and evaluation. The person-based approach involves using mixed methods research to systematically investigate the beliefs, attitudes, needs and situation of the people who will be using the intervention. The in-depth understanding of users' perspectives derived from this research then enables intervention developers to design or modify the intervention to make it more relevant, persuasive, accessible and engaging. The first illustration describes how relevant beliefs and attitudes of people with asthma were identified from the existing qualitative and quantitative literature and then used to create guiding principles to inform the design of a web-based intervention to improve quality of life. The second illustration describes how qualitative "think-aloud" interviews and patient and public involvement (PPI) input are used to improve the acceptability of a booklet for people with asthma. In the third illustration, iterative think-aloud methods are used to create a more accurate and accessible activity planner for people with diabetes. In the first illustration of the person-based approach, we present the guiding principles we developed to summarise key design issues/objectives and key intervention features to address them. The second illustration provides evidence from interviews that positive, non-medical messages and images were preferred in booklet materials for people with asthma. The third illustration demonstrates that people with diabetes found it difficult to complete an online activity planner accurately, resulting in incorrect personalised advice being given prior to appropriate modification of the planner. The person-based approach to intervention development can complement theory- and evidence-based development and participant input into intervention design, offering a systematic process for systematically investigating and incorporating the views of a wide range of users.


Toppled television sets and head injuries in the pediatric population: a framework for prevention.
Injuries to children caused by falling televisions have become more frequent during the last decade. These injuries can be severe and even fatal and are likely to become even more common in the future as TVs increase in size and become more affordable. To formulate guidelines for the prevention of these injuries, the authors systematically reviewed the literature on injuries related to toppling televisions. The authors searched MEDLINE, PubMed, Embase, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane Library, and Google Scholar according to the Cochrane guidelines for all studies involving children 0-18 years of age who were injured by toppled TVs. Factors contributing to injury were categorized using Haddon's Matrix, and the public health approach was used as a framework for developing strategies to prevent these injuries. The vast majority (84%) of the injuries occurred in homes and more than three-fourths were unwitnessed by adult caregivers. The TVs were most commonly large and elevated off the ground. Dressers and other furniture not designed to support TVs were commonly involved in the TV-toppling incident. The case fatality rate varies widely, but almost all deaths reported (96%) were due to brain injuries. Toddlers between the ages of 1 and 3 years most frequently suffer injuries to the head and neck, and they are most likely to suffer severe injuries. Many of these injuries require brain imaging and neurosurgical intervention. Prevention of these injuries will require changes in TV design and legislation as well as increases in public education and awareness. Television-toppling injuries can be easily prevented; however, the rates of injury do not reflect a sufficient level of awareness, nor do they reflect an acceptable effort from an injury prevention perspective.


Low-cost noninvasive optical CO2 sensing system for fermentation and cell culture.
High-throughput bioprocessing is a very promising technique for bioprocess development and optimization because of its high efficiency. The key to its development has been the availability of simple and inexpensive sensors to monitor the bioprocesses conducted in its small-scale bioreactors. Here we report on a low-cost noninvasive CO2 sensing system suitable for any transparent vessel. The system was composed of a CO2 sensing patch, a coaster, an interface, and a computer. The sensing film was prepared using the ion-pair technique. The coaster was a small self-made device with necessary optics and electronics for ratiometric measurements with a component cost of less than dollar 100. Results show that the system was stable and reliable despite its simplicity and low cost. The sensitivity of the CO2 sensing system was not affected by pH, media type, or temperature. It was shown to be stable for at least 10 days, long enough for most bioprocesses.


Autoreactivity to Sulfatide by Human Invariant NKT Cells.
Invariant NKT (iNKT) cells are innate-like lymphocytes that recognize lipid Ags presented by CD1d. The prototypical Ag, α-galactosylceramide, strongly activates human and mouse iNKT cells, leading to the assumption that iNKT cell physiology in human and mouse is similar. In this article, we report the surprising finding that human, but not mouse, iNKT cells directly recognize myelin-derived sulfatide presented by CD1d. We propose that sulfatide is recognized only by human iNKT cells because of the unique positioning of the 3-O-sulfated β-galactose headgroup. Surface plasmon resonance shows that the affinity of human CD1d-sulfatide for the iNKT cell receptor is relatively low compared with CD1d-α-galactosylceramide (KD of 19-26 μM versus 1 μM). Apolipoprotein E isolated from human cerebrospinal fluid carries sulfatide that can be captured by APCs and presented by CD1d to iNKT cells. APCs from patients with metachromatic leukodystrophy, who accumulate sulfatides due to a deficiency in arylsulfatase-A, directly activate iNKT cells. Thus, we have identified sulfatide as a self-lipid recognized by human iNKT cells and propose that sulfatide recognition by innate T cells may be an important pathologic feature of neuroinflammatory disease and that sulfatide in APCs may contribute to the endogenous pathway of iNKT cell activation.


Gold nanorods carrying paclitaxel for photothermal-chemotherapy of cancer.
Nanotechnology-based photothermal therapy has emerged as a promising treatment for cancer during the past decade. However, heterogeneous laser heating and limited light penetration can lead to incomplete tumor cell eradication. Here, we developed a method to overcome these limitations by combining chemotherapy with photothermal therapy using paclitaxel-loaded gold nanorods. Paclitaxel was loaded to gold nanorods with high density (2.0 × 10(4) paclitaxel per gold nanorod) via nonspecific adsorption, followed by stabilization with poly(ethylene glycol) linked with 11-mercaptoundecanoic acid. Paclitaxel was entrapped in the hydrophobic pocket of the polymeric monolayer on the surface of gold nanorods, which allows direct cellular delivery of the hydrophobic drugs via the lipophilic plasma membrane. Highly efficient drug release was demonstrated in a cell membrane mimicking two-phase solution. Combined photothermal therapy and chemotherapy with the paclitaxel-loaded gold nanorods was shown to be highly effective in killing head and neck cancer cells and lung cancer cells, superior to photothermal therapy or chemotherapy alone due to a synergistic effect. The paclitaxel-gold nanorod enabled photothermal chemotherapy has the potential of preventing tumor reoccurrence and metastasis and may have an important impact on the treatment of head and neck cancer and other malignancies in the clinic.


Modelling psychosocial influences on the distress and impairment caused by psychotic-like experiences in children and adolescents.
Psychological understanding of psychotic-like experiences (PLEs) occurring in childhood is limited, with no recognised conceptual framework to guide appropriate intervention. We examined the contribution to PLE severity of emotional, cognitive and socio-environmental mechanisms thought to influence the development and maintenance of psychosis. Forty 8-14 year olds referred to a community Child and Adolescent Mental Health Service completed a battery of questionnaires and assessments measuring severity of PLEs, emotional problems, cognitive biases, and negative life events. 85% of children assessed reported having experienced a PLE over the previous year; and 55% reported more than one. 60% had experienced at least one in the previous fortnight. Multiple linear regression demonstrated that each of the variables made a significant and independent contribution to PLE severity, after adjusting for verbal ability and age, accounting together for more than half of the variance (reasoning B = 6.324, p = .049; emotion B = 1.807, p = .005; life events B = 4.039, p = .001). PLEs were common in this clinical sample of children. Psychological factors implicated in the development and maintenance of psychosis in adults were also associated with PLE severity in these children. PLE severity may be reduced by targeting each of these factors in cognitive therapy, at this very early stage. Any improvements in emotional wellbeing and functioning may then increase future resilience.


Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation.
BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.RESULTSEBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles.CONCLUSIONThird-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation.TRIAL REGISTRATIONPhase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program.FUNDINGThis work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard "Rick" J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.


Potential link between biotic defense activation and recalcitrance to induction of somatic embryogenesis in shoot primordia from adult trees of white spruce (Picea glauca).
Among the many commercial opportunities afforded by somatic embryogenesis (SE), it is the ability to clonally propagate individual plants with rare or elite traits that has some of the most significant implications. This is particularly true for many long-lived species, such as conifers, but whose long generation times pose substantive challenges, including increased recalcitrance for SE as plants age. Identification of a clonal line of somatic embryo-derived trees whose shoot primordia have remained responsive to SE induction for over a decade, provided a unique opportunity to examine the molecular aspects underpinning SE within shoot tissues of adult white spruce trees. Microarray analysis was used to conduct transcriptome-wide expression profiling of shoot explants taken from this responsive genotype following one week of SE induction, which when compared with that of a nonresponsive genotype, led to the identification of four of the most differentially expressed genes within each genotype. Using absolute qPCR to expand the analysis to three weeks of induction revealed that differential expression of all eight candidate genes was maintained to the end of the induction treatment, albeit to differing degrees. Most striking was that both the magnitude and duration of candidate gene expression within the nonresponsive genotype was indicative of an intense physiological response. Examining their putative identities further revealed that all four encoded for proteins with similarity to angiosperm proteins known to play prominent roles in biotic defense, and that their high-level induction over an extended period is consistent with activation of a biotic defense response. In contrast, the more temperate response within the responsive genotype, including induction of a conifer-specific dehydrin, is more consistent with elicitation of an adaptive stress response. While additional evidence is required to definitively establish an association between SE responsiveness and a specific physiological response, these results suggest that biotic defense activation may be antagonistic, likely related to the massive transcriptional and metabolic reprogramming that it elicits. A major issue for future work will be to determine how and if suppressing biotic defense activation could be used to promote a physiological state more conducive to SE induction.


Neural responses to morphological, syntactic, and semantic properties of single words: an fMRI study.
Dissociations in the recognition of specific classes of words have been documented in brain-injured populations. These include deficits in the recognition and production of morphologically complex words as well as impairments specific to particular syntactic classes such as verbs. However, functional imaging evidence for distinctions among the neural systems underlying these dissociations has been inconclusive. We explored the neural systems involved in processing different word classes in a functional Magnetic Resonance Imaging study, contrasting four groups of words co-varying morphological complexity (simple, monomorphemic words vs complex derived or inflected words) and syntactic class (verbs vs nouns/adjectives). Subtraction of word from letter string processing showed activation in left frontal and temporal lobe regions consistent with prior studies of visual word processing. No differences were observed for morphologically complex and simple words, despite adequate power to detect stimulus specific effects. A region of posterior left middle temporal gyrus showed significantly increased activation for verbs. Post hoc analyses showed that this elevated activation could also be related to semantic properties of the stimulus items (verbs have stronger action associations than nouns, and action association is correlated with activation). Results suggest that semantic as well as syntactic factors should be considered when assessing the neural systems involved in single word comprehension.


Indicated prevention with long-chain polyunsaturated omega-3 fatty acids in patients with 22q11DS genetically at high risk for psychosis. Protocol of a randomized, double-blind, placebo-controlled treatment trial.
It has been found that long-chain omega-3 polyunsaturated fatty acids (PUFAs) reduce the risk of progression to first episode of psychosis (FEP) and may offer a safe and efficacious strategy for selective and indicated prevention in young people with ultra-high-risk (UHR) states. An opportunity for exploring the trajectory of FEP and for investigating the efficacy of preventive treatments exists in 22q11.2 deletion syndrome (22q11DS), which has a 30% psychotic transition rate. The fact that 22q11DS patients are more homogeneous than other UHR groups and are characterized by high level of negative symptoms provides a strong rationale for the use of PUFAs. The principal aim of the present trial is to investigate the effects of PUFAs in individuals with 22q11DS who are at UHR for developing FEP. A prospective, randomized, double-blind, placebo-controlled, single-centre study design will be used. Eighty individuals aged 12-26 will be randomly assigned to two treatment conditions. The experimental group will receive PUFAs. The placebo group will receive paraffin oil. Standard clinical assessments and neuropsychological tests will be performed at baseline and at 8-, 12-, 26- and 52-week follow-up. Blood samples will be collected at baseline and after 12 weeks. This study is registered as an International Standard RCT, number 02070211. The corresponding author is supported by a NARSAD Young Investigator Award. This is the protocol of a planned study that aims to test the efficacy of PUFAs in the prodromal phase of FEP, in a specific syndrome where there is strong evidence that a high genetic load is involved in the disorder.


Exploring the movement dynamics of deception.
BOTH THE SCIENCE AND THE EVERYDAY PRACTICE OF DETECTING A LIE REST ON THE SAME ASSUMPTION: hidden cognitive states that the liar would like to remain hidden nevertheless influence observable behavior. This assumption has good evidence. The insights of professional interrogators, anecdotal evidence, and body language textbooks have all built up a sizeable catalog of non-verbal cues that have been claimed to distinguish deceptive and truthful behavior. Typically, these cues are discrete, individual behaviors-a hand touching a mouth, the rise of a brow-that distinguish lies from truths solely in terms of their frequency or duration. Research to date has failed to establish any of these non-verbal cues as a reliable marker of deception. Here we argue that perhaps this is because simple tallies of behavior can miss out on the rich but subtle organization of behavior as it unfolds over time. Research in cognitive science from a dynamical systems perspective has shown that behavior is structured across multiple timescales, with more or less regularity and structure. Using tools that are sensitive to these dynamics, we analyzed body motion data from an experiment that put participants in a realistic situation of choosing, or not, to lie to an experimenter. Our analyses indicate that when being deceptive, continuous fluctuations of movement in the upper face, and somewhat in the arms, are characterized by dynamical properties of less stability, but greater complexity. For the upper face, these distinctions are present despite no apparent differences in the overall amount of movement between deception and truth. We suggest that these unique dynamical signatures of motion are indicative of both the cognitive demands inherent to deception and the need to respond adaptively in a social context.


Large-scale forest restoration stabilizes carbon under climate change in Southwest United States.
Higher tree density, more fuels, and a warmer, drier climate have caused an increase in the frequency, size, and severity of wildfires in western U.S. forests. There is an urgent need to restore forests across the western United States. To address this need, the U.S. Forest Service began the Four Forest Restoration Initiative (4FRI) to restore four national forests in Arizona. The objective of this study was to evaluate how restoration of ~400,000 ha under the 4FRI program and projected climate change would influence carbon dynamics and wildfire severity from 2010 to 2099. Specifically, we estimated forest carbon fluxes, carbon pools and wildfire severity under a moderate and fast 4FRI implementation schedule and compared those to status quo and no-harvest scenarios using the LANDIS-II simulation model and climate change projections. We found that the fast-4FRI scenario showed early decreases in ecosystem carbon due to initial thinning/prescribed fire treatments, but total ecosystem carbon increased by 9-18% over no harvest by the end of the simulation. This increased carbon storage by 6.3-12.7 million metric tons, depending on the climate model, equating to removal of carbon emissions from 55,000 to 110,000 passenger vehicles per year until the end of the century. Nearly half of the additional carbon was stored in more stable soil pools. However, climate models with the largest predicted temperature increases showed declines by late century in ecosystem carbon despite restoration. Our study uses data from a real-world, large-scale restoration project and indicates that restoration is likely to stabilize carbon and the benefits are greater when the pace of restoration is faster.


Use of nanotopography to study mechanotransduction in fibroblasts--methods and perspectives.
The environment around a cell during in vitro culture is unlikely to mimic those in vivo. Preliminary experiments with nanotopography have shown that nanoscale features can strongly influence cell morphology, adhesion, proliferation and gene regulation, but the mechanisms mediating this cell response remain unclear. In this perspective article, we attempt to illustrate that a possible mechanism is direct transmittal of forces encountered by cells during spreading to the nucleus via the cytoskeleton. We further try to illustrate that this 'self-induced' mechanotransduction may alter gene expression by changing interphase chromosome positioning. Whilst the observations described here to show how we think nanotopography can be developed as a tool to look at mechanotransduction are preliminary, we feel they indicate that topography may give cell biologists a non-invasive tool with which to investigate in vitro cellular mechanisms.


Ecosystem recovery after climatic extremes enhanced by genotypic diversity.
Contemporary climate change is characterized both by increasing mean temperature and increasing climate variability such as heat waves, storms, and floods. How populations and communities cope with such climatic extremes is a question central to contemporary ecology and biodiversity conservation. Previous work has shown that species diversity can affect ecosystem functioning and resilience. Here, we show that genotypic diversity can replace the role of species diversity in a species-poor coastal ecosystem, and it may buffer against extreme climatic events. In a manipulative field experiment, increasing the genotypic diversity of the cosmopolitan seagrass Zostera marina enhanced biomass production, plant density, and faunal abundance, despite near-lethal water temperatures due to extreme warming across Europe. Net biodiversity effects were explained by genotypic complementarity rather than by selection of particularly robust genotypes. Positive effects on invertebrate fauna suggest that genetic diversity has second-order effects reaching higher trophic levels. Our results highlight the importance of maintaining genetic as well as species diversity to enhance ecosystem resilience in a world of increasing uncertainty.


Racial/ethnic disparities in nursing.
The racial and ethnic composition of the registered nurse (RN) workforce in California is not at parity with the composition of the population. We find that the underrepresentation of African Americans in nursing in California appears to be due to lower overall educational attainment among African Americans. Underrepresentation of Latinos is due to lower overall educational attainment and, to a lesser extent, a lower percentage of college-educated Latinos pursuing careers in nursing. Improving the overall educational attainment of minority students is critical to increasing the number of minorities in nursing.


Transition State Structure of RNA Depurination by Saporin L3.
Saporin L3 from the leaves of the common soapwort is a catalyst for hydrolytic depurination of adenine from RNA. Saporin L3 is a type 1 ribosome inactivating protein (RIP) composed only of a catalytic domain. Other RIPs have been used in immunotoxin cancer therapy, but off-target effects have limited their development. In the current study, we use transition state theory to understand the chemical mechanism and transition state structure of saporin L3. In favorable cases, transition state structures guide the design of transition state analogues as inhibitors. Kinetic isotope effects (KIEs) were determined for an A14C mutant of saporin L3. To permit KIE measurements, small stem-loop RNAs that contain an AGGG tetraloop structure were enzymatically synthesized with the single adenylate bearing specific isotopic substitutions. KIEs were measured and corrected for forward commitment to obtain intrinsic values. A model of the transition state structure for depurination of stem-loop RNA (5'-GGGAGGGCCC-3') by saporin L3 was determined by matching KIE values predicted via quantum chemical calculations to a family of intrinsic KIEs. This model indicates saporin L3 displays a late transition state with the N-ribosidic bond to the adenine nearly cleaved, and the attacking water nucleophile weakly bonded to the ribosyl anomeric carbon. The transition state retains partial ribocation character, a feature common to most N-ribosyl transferases. However, the transition state geometry for saporin L3 is distinct from ricin A-chain, the only other RIP whose transition state is known.


Germline mutation screening of the Saethre-Chotzen-associated genes TWIST1 and FGFR3 in families with BRCA1/2-negative breast cancer.
Saethre-Chotzen syndrome is one of the most common craniosynostosis syndromes. It is an autosomal dominantly inherited disorder with variable expression that is caused by germline mutations in the TWIST1 gene or more rarely in the FGFR2 or FGFR3 genes. We have previously reported that patients with Saethre-Chotzen syndrome have an increased risk of developing breast cancer. Here we have analysed a cohort of 26 women with BRCA1/2-negative hereditary breast cancer to study whether a proportion of these families might have mutations in Saethre-Chotzen-associated genes. DNA sequence analysis of TWIST1 showed no pathogenic mutations in the coding sequence in any of the 26 patients. MLPA (multiplex ligation-dependent probe amplification)-analysis also showed no alterations in copy numbers in any of the craniofacial disorder genes MSX2, ALX4, RUNX2, EFNB1, TWIST1, FGFR1, FGFR2,FGFR3, or FGFR4. Taken together, our findings indicate that mutations in Saethre-Chotzen-associated genes are uncommon or absent in BRCA1/2-negative patients with hereditary breast cancer.


Protein domain microarrays as a platform to decipher signaling pathways and the histone code.
Signal transduction is driven by protein interactions that are controlled by posttranslational modifications (PTM). Usually, protein domains are responsible for "reading" the PTM signal deposited on the interacting partners. Protein domain microarrays have been developed as a high throughput platform to facilitate the rapid identification of protein-protein interactions, and this approach has become broadly used in biomedical research. In this review, we will summarize the history, development and applications of this technique, including the use of protein domain microarrays in identifying both novel protein-protein interactions and small molecules that block these interactions. We will focus on the approaches we use in the Protein Array and Analysis Core - the PAAC - at MD Anderson Cancer Center. We will also address the technical limitations and discuss future directions.


Differential frequency of NKG2C/KLRC2 deletion in distinct African populations and susceptibility to Trachoma: a new method for imputation of KLRC2 genotypes from SNP genotyping data.
NKG2C is an activating receptor that is preferentially expressed on natural killer (NK) cells. The gene encoding NKG2C (killer cell lectin-like receptor C2, KLRC2) is present at different copy numbers in the genomes of different individuals. Deletion at the NKG2C locus was investigated in a case-control study of 1522 individuals indigenous to East- and West-Africa and the association with the ocular Chlamydia trachomatis infection and its sequelae was explored. The frequency of homozygous KLRC2 deletion was 13.7 % in Gambians and 4.7 % in Tanzanians. A significantly higher frequency of the deletion allele was found in West-Africans from the Gambia and Guinea-Bissau (36.2 % p = 2.105 × 10(-8), 26.8 % p = 0.050; respectively) in comparison to East-African Tanzanians where the frequency of the deletion is comparable to other human populations (20.9 %). We found no evidence for an association between the numbers of KLRC2 gene copies and the clinical manifestations of trachoma (follicular trachoma or conjunctival scarring). A new method for imputation of KLRC2 genotypes from single nucleotide polymorphism (SNP) data in 2621 individuals from the Gambia further confirmed these results. Our data suggest that NKG2C does not play a major role in trachomatous disease. We found that the deletion allele is present at different frequencies in different populations but the reason behind these differences is currently not understood. The new method offers the potential to use SNP arrays from genome wide association studies to study the frequency of KLRC2 deletion in other populations and its association with other diseases.


Effects of Insulin and High Glucose on Human Meibomian Gland Epithelial Cells.
Type 2 diabetes is a risk factor for meibomian gland dysfunction (MGD). We hypothesize that this diabetic impact is due, at least in part, to the effects of insulin resistance/deficiency and hyperglycemia on human meibomian gland epithelial cells (HMGECs). To begin to test this hypothesis, we examined whether insulin and high glucose influence immortalized (I) HMGECs. Immortalized HMGECs were cultured in serum-containing or -free media and treated with insulin, insulin-like growth factor-1 (IGF-1), IGF-1 receptor (R) blocking antibody, and glucose or mannitol for varying time periods. Specific proteins were detected by Western blots, cell proliferation was evaluated by manual cell counting and lipids were assessed with LipidTOX and high performance thin layer chromatography. We found that insulin induces a dose-dependent increase in phosphatidylinositide 3-kinase/Akt (AKT) signaling in IHMGECs. This effect involves the IGF-1R, but not the insulin receptor (IR), and is associated with a stimulation of cell proliferation and neutral lipid accumulation. In contrast, high glucose exposure alters cell morphology, causes a progressive cell loss, and significantly reduces the levels of IGF-1R, phospho (p)-AKT, Foxhead box protein O1 (FOXO1), and sterol-regulatory element binding protein (SREBP-1) in IHMGECs. Our data show that insulin stimulates, and that high glucose is toxic for, IHMGECs. These results support our hypothesis that insulin resistance/deficiency and hyperglycemia are deleterious for HMGECs and may help explain why type II diabetes is a risk factor for MGD.


HIV-positive parents, HIV-positive children, and HIV-negative children's perspectives on disclosure of a parent's and child's illness in Kenya.
HIV disclosure from parent to child is complex and challenging to HIV-positive parents and healthcare professionals. The purpose of the study was to understand the lived experiences of HIV-positive parents and their children during the disclosure process in Kenya. Sixteen HIV-positive parents, seven HIV-positive children, and five HIV-negative children completed semistructured, in-depth interviews. Data were analyzed using the Van Kaam method; NVivo 8 software was used to assist data analysis. We present data on the process of disclosure based on how participants recommended full disclosure be approached to HIV-positive and negative children. Participants recommended disclosure as a process starting at five years with full disclosure delivered at 10 years when the child was capable of understanding the illness, or by 14 years when the child was mature enough to receive the news if full disclosure had not been conducted earlier. Important considerations at the time of full disclosure included the parent's and/or child's health statuses, number of infected family members' illnesses to be disclosed to the child, child's maturity and understanding level, and the person best suited to deliver full disclosure to the child. The results also revealed it was important to address important life events such as taking a national school examination during disclosure planning and delivery. Recommendations are made for inclusion into HIV disclosure guidelines, manuals, and programs in resource-poor nations with high HIV prevalence.


Growth hormone response to arginine test differentiates between two subgroups of Huntington's disease patients.
Huntington's disease (HD) is an autosomal dominant disorder characterised by motor, cognitive and psychiatric disturbances. Several studies have demonstrated that hypothalamic dysfunction is part of the phenotypic spectrum. The aim of the study was to evaluate the growth hormone (GH) response to arginine infusion in a cohort of HD patients, to search for an in vivo biomarker of hypothalamic dysfunction. The authors investigated 17 HD patients and 17 age-, sex- and BMI-matched healthy controls. Clinical assessment of patients was performed using the Unified Huntington's Disease Rating Scale motor section and total function capacity. Metabolic and endocrine investigations included total, LDL and HDL cholesterol, basal insulin, GH, insulin-like growth factor 1 (IGF-1), SD Score IGF-1 (SDS IGF-1) and the GH response to arginine stimulation. HD patients showed lower plasma IGF-1 and SDS IGF-1 levels and a higher baseline GH in comparison with control subjects. The arginine test induced a normal GH peak in nine patients (53%; Arg+), whereas the response was absent in the remaining eight (47%; Arg-). Arg+ and Arg- also showed two distinct endocrine/metabolic profiles with differences in insulin and lipid metabolism. It remains to be clarified if these two subgroups of patients, according to the GH response to arginine, correspond to different disease stages or to different patterns of neurodegeneration.


Pornography Consumption, Modality and Function in a Large Internet Sample.
Pornography consumption research often contains measurement inconsistencies that make the literature difficult to integrate. We investigated measurement issues relating to four key areas of pornography research simultaneously in a single data set: (a) differential endorsement across commonly used pornography consumption measures; (b) common modalities of pornography use (e.g., pictures, videos); (c) function of pornography use; and (d) association of age and gender with the above. The sample (n = 1,392) of adults in the United States was collected using Amazon Mechanical Turk and included a much wider age range (ages 18-73) than in typical pornography research. Using all modalities of pornography, 91.5% of men and 60.2% of women herein reported having consumed pornography in the past month. The three primary modalities of pornography consumed were written pornography, pictures, and videos. Videos were consumed most often, but women were much more likely to consume written pornography than men. The primary function of viewing pornography was to enhance masturbation, but notably there was endorsement of many other uses. Cross-sectional age trends and gender differences are discussed with suggestions for future research. Empirical concerns for research in pornography are addressed, with special attention to considerations for estimates of pornography consumption rates and research definitions of pornography.


Improvement of secondary fixed dystonia of the upper limb after chronic extradural motor cortex stimulation in 10 patients: first reported series.
Fixed dystonic postures secondary to ischemic, traumatic, or postsurgical lesions located in the basal ganglia and brainstem constitute a major therapeutic challenge and limit motor rehabilitation efficacy. They are often refractory to conservative treatment. Aberrant cerebral plasticity developed after deep brain lesions is thought to lead to abnormal cortical representation of the affected part of the body and then to pathological fixed postures. To assess the efficacy of motor cortex stimulation in patients with upper limb fixed dystonia. Ten patients were submitted to computer-assisted and electromyography-monitored implantation of intracranial epidural electrodes over the central cortical sulcus contralateral to the affected limb. Patients were followed up from 1 to 9 years (9 patients), except for patient 10, whose follow-up was limited to 4 months. Seven of 7 patients showed > 30% improvement in the Disability of Shoulder, Arm, and Hand Scale and an overall 70% increase in the score of the Short Form-36 Physical Activity subscale with significant and stable improvement of quality of life during stimulation. The partial recovery of hand dexterity observed in most of the treated patients additionally contributed to a significant improvement of their quality of life. Although the pathophysiology of fixed dystonia is unknown, our results suggest a major role of the motor cortex in this condition and reinforce the hypothesis that postlesional delayed cortical rearrangements might take place in these forms and be the target of effective therapeutic neuromodulation.


National patterns in antidepressant treatment by psychiatrists and general medical providers: results from the national comorbidity survey replication.
Primary care physicians, rather than psychiatrists, prescribe a majority of psychotropic medications in the United States. However, past research has shown significant differences in psychopharmacologic treatment practices of these 2 groups of physicians. The objective of this study was to compare patient characteristics and treatment patterns of adults in the United States treated with antidepressant medications by psychiatrists and other medical providers. Data from the National Comorbidity Survey Replication (February 2001-April 2003) were used to compare characteristics of adults (aged >/= 18 years) prescribed antidepressants by psychiatrists (N = 255) or other medical providers (N = 673). The treatment groups were also compared with respect to presenting problem, antidepressant type and dose, and continuity of treatment. Approximately 1 in 10 adults (10.5%) were treated with an antidepressant in the past year, usually by a general medical provider (73.6%). Compared with those treated by psychiatrists, adults treated by general medical providers were significantly more likely to be at least 65 years of age and to reside in a nonurban area. By contrast, those treated by psychiatrists were significantly more likely to be male, to report significant distress, to present with serious mood or anxiety symptoms, and to meet DSM-IV criteria for mood and anxiety disorders. Individuals treated by psychiatrists typically received higher doses of medications, were less likely to stop the medication before 30 days, and were more likely to continue 90 days or longer. Most adults treated with anti-depressants receive the medication from general medical providers. In comparison with adults treated by psychiatrists, those treated by general medical providers are less likely to meet the criteria for mood or anxiety disorders or to continue medication beyond the first month. Quality improvement initiatives in general medical settings should focus on better targeting and continuity of antidepressant medications.


Increased erythrocyte adhesion in mice and humans with hereditary spherocytosis and hereditary elliptocytosis.
Mice with disruptions of the red blood cell (RBC) cytoskeleton provide severe hemolytic anemia models in which to study multiorgan thrombosis and infarction. The incidence of cerebral infarction ranges from 70% to 100% in mice with alpha-spectrin deficiency. To determine whether mutant RBCs abnormally bind adhesive vascular components, we measured adhesion of mouse and human RBCs to immobilized human thrombospondin (TSP) and laminin (LM) under controlled flow conditions. Mutant RBCs had at least 10-fold higher adhesion to TSP compared with normal RBCs (P <.006). Mutant relative to unaffected RBC adhesion to LM was significantly (P <.01) increased as well. Treatment of RBCs with the anionic polysaccharide dextran sulfate inhibited mutant RBC adhesion to TSP (P <.001). Treatment of RBCs with antibodies to CD47 or the CD47-binding TSP peptide 4N1K did not inhibit TSP adhesion of RBCs. Previously, we have shown that infarcts in alpha-spectrin-deficient sph/sph mice become histologically evident beginning at 6 weeks of age. TSP adhesion of RBCs from 3- to 4- and 6- to 8-week-old sph/sph mice was significantly higher than RBCs from adult mice (> 12 weeks old; P <.005). While the mechanism of infarction in these mice is unknown, we speculate that changes in RBC adhesive characteristics contribute to this pathology.


IL-15 regulates susceptibility of CD4+ T cells to HIV infection.
HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4+ memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible to HIV infection, making them a key component of the reservoir itself. IL-15 is up-regulated during primary HIV infection, a time when the HIV reservoir established. Therefore, we investigated the molecular and cellular impact of IL-15 on CD4+ T-cell infection. We found that IL-15 stimulation induces SAM domain and HD domain-containing protein 1 (SAMHD1) phosphorylation due to cell cycle entry, relieving an early block to infection. Perturbation of the pathways downstream of IL-15 receptor (IL-15R) indicated that SAMHD1 phosphorylation after IL-15 stimulation is JAK dependent. Treating CD4+ T cells with Ruxolitinib, an inhibitor of JAK1 and JAK2, effectively blocked IL-15-induced SAMHD1 phosphorylation and protected CD4+ T cells from HIV infection. Using high-resolution single-cell immune profiling using mass cytometry by TOF (CyTOF), we found that IL-15 stimulation altered the composition of CD4+ T-cell memory populations by increasing proliferation of memory CD4+ T cells, including CD4+ T memory stem cells (TSCM). IL-15-stimulated CD4+ TSCM, harboring phosphorylated SAMHD1, were preferentially infected. We propose that IL-15 plays a pivotal role in creating a self-renewing, persistent HIV reservoir by facilitating infection of CD4+ T cells with stem cell-like properties. Time-limited interventions with JAK1 inhibitors, such as Ruxolitinib, should prevent the inactivation of the endogenous restriction factor SAMHD1 and protect this long-lived CD4+ T-memory cell population from HIV infection.


Spatial regulation of BMP signaling by patterned receptor expression.
Local delivery of TGF-beta/BMP ligands is commonly used as a tissue engineering strategy for the spatial regulation of cell growth and differentiation. While the location and the dose of ligand are the only parameters that influence the spatial distribution and biological effects of the ligand in vitro, in vivo genetic studies of development reveal that spatial control of TGF-beta/BMP signaling can be accomplished at multiple levels, from ligand release to signal interpretation. Here we focus on spatial control of BMP signaling by patterned receptor expression. Motivated by our recent experimental analysis of the two-dimensional BMP signaling patterns in the developing Drosophila egg, we formulate one- and two-dimensional models of ligand diffusion and internalization in the presence of patterned receptor expression. Our analysis of these models shows that they can capture the quantitative features of the experimentally observed pattern of phosphorylated SMAD in Drosophila oogenesis and shows that patterned receptor expression provides versatile control of BMP signaling in developing tissues. Quantitative understanding of the mechanisms of spatiotemporal control of signaling pathways in development is essential for successful harnessing of these pathways in tissue engineering.


Meditative movement for respiratory function: a systematic review.
Meditative movement, such as tai chi, yoga, and qi gong, may benefit people with cystic fibrosis (CF), as a form of gentle exercise incorporating meditation, breathing, and relaxation. Respiratory function is the most common issue in CF. In this systematic review we synthesized the evidence on the effect of meditative movement on respiratory function in patients with CF. We searched Chinese and English language databases with terms relating to tai chi/yoga/qi gong, and respiratory function/cough/dyspnea. Articles were screened and selected by 2 researchers. We included controlled studies published in English or Chinese after 1980, and extracted data using a specially designed spreadsheet. Two researchers independently evaluated study quality and reporting, using 3 standardized checklists. Meta-analysis was not possible due to heterogeneous methods. We found 1,649 papers, included 43 (30 in English, 13 in Chinese), 23 of which were randomized controlled trials, and 20 were non-randomized trials. No studies were concerned with CF. Eleven studies included patients with respiratory disorders, and 27 included healthy people. Very few studies were high quality. The main problems with the randomized controlled trials was the randomization and non-random and/or poorly reported sampling. The main problems with the non-randomized studies were poor reporting of samples and non-equivalent groups. Although no clinically important changes were found, meditative movement may improve FEV1 in healthy people, compared to no treatment/exercise (the intervention groups showed effect-size changes from 0.07 to 0.83), but meditative movement did not appear to affect FEV1/FVC in subjects with COPD. Key study limitations were: poor reporting of sampling or methods; inadequate sample size; non-randomized design; inadequate description of randomization; randomization by center; no blinding; lack of reporting of important aspects of meditative movement; and short-term follow-up. The available evidence does not support meditative movement for patients with CF, and there is very limited evidence for respiratory function in healthy populations. The available studies had heterogeneous populations and provided inadequate sampling information, so clinically relevant conclusions cannot be drawn. Well powered, randomized studies of meditative movement are needed.


Evolutionary study and phylodynamic pattern of human influenza A/H3N2 virus in Indonesia from 2008 to 2010.
Influenza viruses are by nature unstable with high levels of mutations. The sequential accumulation of mutations in the surface glycoproteins allows the virus to evade the neutralizing antibodies. The consideration of the tropics as the influenza reservoir where viral genetic and antigenic diversity are continually generated and reintroduced into temperate countries makes the study of influenza virus evolution in Indonesia essential. A total of 100 complete coding sequences (CDS) of Hemagglutinin (HA) and Neuraminidase (NA) genes of H3N2 virus were obtained from archived samples of Influenza-Like Illness (ILI) surveillance collected from 2008 to 2010. Our evolutionary and phylogenetic analyses provide insight into the dynamic changes of Indonesian H3N2 virus from 2008 to 2010. Obvious antigenic drift with typical 'ladder-like' phylogeny was observed with multiple lineages found in each year, suggesting co-circulation of H3N2 strains at different time periods. The mutational pattern of the Indonesian H3N2 virus was not geographically related as relatively low levels of mutations with similar pattern of relative genetic diversity were observed in various geographical origins. This study reaffirms that the existence of a particular lineage is most likely the result of adaptation or competitive exclusion among different host populations and combination of stochastic ecological factors, rather than its geographical origin alone.


From Water Oxidation to Reduction: Transformation from Ni(x)Co(3-x)O4 Nanowires to NiCo/NiCoO(x) Heterostructures.
A homologous Ni-Co based nanowire catalyst pair, composed of Ni(x)Co(3-x)O4 nanowires and NiCo/NiCoO(x) nanohybrid, is developed for efficient overall water splitting. Ni(x)Co(3-x)O4 nanowires are found as a highly active oxygen evolution reaction (OER) catalyst, and they are converted into a highly active hydrogen evolution reaction (HER) catalyst through hydrogenation treatment as NiCo/NiCoO(x) heteronanostructures. An OER current density of 10 mA cm(-2) is obtained with the Ni(x)Co(3-x)O4 nanowires under an overpotential of 337 mV in 1.0 M KOH, and an HER current density of 10 mA cm(-2) is obtained with the NiCo/NiCoO(x) heteronanostructures at an overpotential of 155 mV. When integrated in an electrolyzer, these catalysts demonstrate a stable performance in water splitting.


Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells.
Recent studies have implicated mitochondrial reactive oxygen species (ROS) in regulating hypoxic pulmonary vasoconstriction (HPV), but controversy exists regarding whether hypoxia increases or decreases ROS generation. This study tested the hypothesis that hypoxia induces redox changes that differ among subcellular compartments in pulmonary (PASMCs) and systemic (SASMCs) smooth muscle cells. We used a novel, redox-sensitive, ratiometric fluorescent protein sensor (RoGFP) to assess the effects of hypoxia on redox signaling in cultured PASMCs and SASMCs. Using genetic targeting sequences, RoGFP was expressed in the cytosol (Cyto-RoGFP), the mitochondrial matrix (Mito-RoGFP), or the mitochondrial intermembrane space (IMS-RoGFP), allowing assessment of oxidant signaling in distinct intracellular compartments. Superfusion of PASMCs or SASMCs with hypoxic media increased oxidation of both Cyto-RoGFP and IMS-RoGFP. However, hypoxia decreased oxidation of Mito-RoGFP in both cell types. The hypoxia-induced oxidation of Cyto-RoGFP was attenuated through the overexpression of cytosolic catalase in PASMCs. These results indicate that hypoxia causes a decrease in nonspecific ROS generation in the matrix compartment, whereas it increases regulated ROS production in the IMS, which diffuses to the cytosol of both PASMCs and SASMCs.


Localized in vivo 13C NMR spectroscopy of the brain.
Localized (13)C NMR spectroscopy provides a new investigative tool for studying cerebral metabolism. The application of (13)C NMR spectroscopy to living intact humans and animals presents the investigator with a number of unique challenges. This review provides in the first part a tutorial insight into the ingredients required for achieving a successful implementation of localized (13)C NMR spectroscopy. The difficulties in establishing (13)C NMR are the need for decoupling of the one-bond (13)C-(1)H heteronuclear J coupling, the large chemical shift range, the low sensitivity and the need for localization of the signals. The methodological consequences of these technical problems are discussed, particularly with respect to (a) RF front-end considerations, (b) localization methods, (c) the low sensitivity, and (d) quantification methods. Lastly, some achievements of in vivo localized (13)C NMR spectroscopy of the brain are reviewed, such as: (a) the measurement of brain glutamine synthesis and the feasibility of quantifying glutamatergic action in the brain; (b) the demonstration of significant anaplerotic fluxes in the brain; (c) the demonstration of a highly regulated malate-aspartate shuttle in brain energy metabolism and isotope flux; (d) quantification of neuronal and glial energy metabolism; and (e) brain glycogen metabolism in hypoglycemia in rats and humans. We conclude that the unique and novel insights provided by (13)C NMR spectroscopy have opened many new research areas that are likely to improve the understanding of brain carbohydrate metabolism in health and disease.


Are invasive populations characterized by a broader diet than native populations?
Invasive species are among the most significant threats to biodiversity. The diet of invasive animal populations is a crucial factor that must be considered in the context of biological invasions. A broad dietary spectrum is a frequently cited characteristic of invasive species, allowing them to thrive in a wide range of environments. Therefore, empirical studies comparing diet in invasive and native populations are necessary to understand dietary requirements, dietary flexibility, and the associated impacts of invasive species. In this study, we compared the diet of populations of the African clawed frog, Xenopus laevis in its native range, with several areas where it has become invasive. Each prey category detected in stomach contents was assigned to an ecological category, allowing a comparison of the diversity of ecological traits among the prey items in the diet of native and introduced populations. The comparison of diets was also performed using evenness as a niche breadth index on all sampled populations, and electivity as a prey selection index for three out of the six sampled populations. Our results showed that diet breadth could be either narrow or broad in invasive populations. According to diet and prey availability, zooplankton was strongly preferred in most cases. In lotic environments, zooplankton was replaced by benthic preys, such as ephemeropteran larvae. The relative proportions of prey with different ecological traits, and dietary variability within and between areas of occurrence, suggest that X. laevis is a generalist predator in both native and invasive populations. Shifts in the realized trophic niche are observed, and appear related to resource availability. Xenopus laevis may strongly impact aquatic ecosystems because of its near complete aquatic lifestyle and its significant consumption of key taxa for the trophic relationships in ponds.


Reexamination of a measurement for sexual determination using the supero-inferior femoral neck diameter in a modern European population.
The present study reexamines the accuracy of the supero-inferior femoral neck diameter for the determination of sex using a modern sample of French individuals. In 1998, Seidemann et al. used this univariate method for sex determination with the Hamann-Todd collection. Stojanowski and Seidemann in 1999 tested previous results on a modern sample taken from the University of New Mexico and concluded that the Caucasian male samples exhibited no significant differences between individuals born before and after 1900, but the Caucasian female subgroup did exhibit differences with an increase of the SID in the modern sample. The current study compares the previous results of the supero-inferior femoral neck diameter with a modern sample of elderly French individuals born after 1910. Both sides of the femur were measured. No statistical difference was found between the right and left side (p = 0.31). The results showed a significant difference between the pre-1900 and the modern sample, with an increase in femoral neck diameter in modern populations. The comparison of the SID values between the two modern samples (Mexico and Nice) showed no significant differences in the femoral neck diameter in the two male subgroups (p = 0.05), but the measurements of the SID in the female subgroup did exhibit significant differences with an increase of the neck femoral diameter (p < 0.01) in the modern French population. These results demonstrate an increase in the neck femoral morphology in the elderly European French females samples.


Unusual side effect from a luteinizing hormone-releasing hormone agonist, leuprorelin, in the treatment of prostate cancer: a case report.
The treatment options for high-risk prostate cancer are either radical prostatectomy or radiotherapy/brachytherapy depending on the patients' prognosis. In older men with multiple comorbidities, radiotherapy with androgen deprivation therapy is an attractive option. Common side effects of androgen deprivation therapy include hot flushes, tiredness, increased risk of fractures, increased risk of metabolic disorders, coronary heart disease, and psychological effects. This case highlights the potential side effect of lipodystrophy secondary to leuprolide acetate injections. To the best of our knowledge, this is the first reported case of such an instance. In this case report, we describe a 70-year-old white man with prostate-specific antigen of 1.8 ng/mL, clinical stage T2bN0M0, Gleason 4+5=9 prostate cancer who developed an unusual side effect from leuprolide acetate as part of his androgen deprivation therapy. Approximately 2 months after the initial 3-monthly injection of leuprolide acetate (Eligard 22.5 mg) our patient developed abnormal lipid deposition particularly in his deltoid and abdominal region. His upper limb mobility gradually became compromised due to the size of these abnormal fat depositions. He had liposuction to correct this lipodystrophy and had a good functional outcome and cosmesis from the procedure. To the best of our knowledge, this is the first reported case of lipodystrophy secondary to leuprolide acetate injections. Leuprolide acetate in commonly used as one of the gonadotrophin-releasing hormone agonists and thus we should be mindful of the potential effect of producing lipodystrophy, especially in patients with cirrhosis, and to watch for any signs and symptoms as appropriate. The implication of this potential side effect poses difficult management strategies for such patients, and second-line alternatives such as chemotherapy may need to be considered.


Pattern of drugs of abuse identified in chemical samples.
To determine the pattern of drugs of abuse in urine and blood samples processed at referral laboratory in Pakistan so that information on the type of drugs used can be identified and used for ready reference for future strategy. Observational study. Clinical Laboratory of The Aga Khan University Hospital, Karachi, from July 2006 to March 2008. Retrospective review of records were done for the common drugs that are used for screening at the Clinical Laboratory include alcohol, amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine and opiates. Alcohol was tested in blood and others were identified using urine. Percentages of tests screened positive and negative for individual drugs were computed by using SPSS 16.0. The ratio between male and female users was also established. A total of 17,714 tests were performed for drugs. The mean age of the patients whose samples were processed was 30+/-14.84 years. Majority used benzodiazepines 520/1317 (39.5%) among the samples tested for drug of abuse, followed by cannabinoids 423/5450 (7.8%), alcohol 75/1302 (5.8%), barbiturates 32/1148 (2.8%), opiates 137/5640 (2.4%), cocaine 5/1655 (0.3%) and amphetamine 3/1202 (0.2%). In all, males 15411 (87%) were tested more frequently as compared to females 2303 (13%). Males were more frequently tested for drug abuse; however, drug abuse is increasingly seen among females. Benzodiazepines are the most frequently used. The same pattern of drugs abuse existed in different gender and age group. There is a need to explore the pattern and type of drug abuse on national scale.


Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement.
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.


Shoulder girdle rotation, forelimb movement and the influence of carapace shape on locomotion in Testudo hermanni (Testudinidae).
Studies into the function of structures are crucial for making connections between morphology and behaviour of organisms, but are still rare for the terrestrial Testudinidae. We investigated the kinematics of shoulder girdle and forelimb motion in Hermann's tortoise Testudo hermanni using biplanar X-ray fluoroscopy with a twofold aim: firstly, to understand how the derived shapes of shoulder girdle and carapace together influence rotation of the girdle; and, secondly, to understand how girdle rotation affects forelimb excursion. The total degree of shoulder rotation in the horizontal plane is similar to a species with a less domed shell, but because of the long and nearly vertically oriented scapular prong, shoulder girdle rotation contributes more than 30% to the horizontal arc of the humerus and nearly 40% to the rotational component of step length. The antebrachium and manus, which act as a functional unit, contribute roughly 50% to this component of the step length because of their large excursion almost parallel to the mid-sagittal plane. This large excursion is the result of the complex interplay between humerus long-axis rotation, counter-rotation of the antebrachium, and elbow flexion and extension. A significant proportion of forelimb step length results from body translation that is due to the propulsive effect of the other limbs during their stance phases. Traits that are similar to other tortoises and terrestrial or semi-aquatic turtles are the overall slow walk because of a low stride frequency, and the lateral-sequence, diagonally coupled footfall pattern with high duty factors. Intraspecific variation of carapace shape and shoulder girdle dimensions has a corresponding effect on forelimb kinematics.


Hybrid genotypes in the pathogenic yeast Cryptococcus neoformans.
Amplified fragment length polymorphism (AFLP) genotyping of isolates of the pathogenic fungus Cryptococcus neoformans suggested a considerable genetic divergence between the varieties C. neoformans var. neoformans and C. neoformans var. grubii on the one hand versus C. neoformans var. gattii on the other. This divergence is supported by additional phenotypic, biochemical, clinical and molecular differences. Therefore, the authors propose the existence of two species, C. neoformans (Sanfelice) Vuillemin and C. bacillisporus Kwon-Chung, which differ in geographical distribution, serotypes and ecological origin. Within each species three AFLP genotypes occur, which differ in geographical distribution and serotypes. Differences in ecological origin (AIDS patients, non-AIDS patients, animals or the environment) were found to be statistically not significant. In C. neoformans as well as in C. bacillisporus one of the genotypes represented a hybrid. The occurrence of hybridization has consequences for the reproductive biology of the species, as new genotypes with altered virulence or susceptibility to antifungal drugs may arise through the exchange of genetic material.


Perinatal Maternal Mental Health, Fetal Programming and Child Development.
Maternal mental disorders over pregnancy show a clear influence on child development. This review is focused on the possible mechanisms by which maternal mental disorders influence fetal development via programming effects. This field is complex since mental health symptoms during pregnancy vary in type, timing and severity and maternal psychological distress is often accompanied by higher rates of smoking, alcohol use, poor diet and lifestyle. Studies are now beginning to examine fetal programming mechanisms, originally identified within the DOHaD framework, to examine how maternal mental disorders impact fetal development. Such mechanisms include hormonal priming effects such as elevated maternal glucocorticoids, alteration of placental function and perfusion, and epigenetic mechanisms. To date, mostly high prevalence mental disorders such as depression and anxiety have been investigated, but few studies employ diagnostic measures, and there is very little research examining the impact of maternal mental disorders such as schizophrenia, bipolar disorder, eating disorders and personality disorders on fetal development. The next wave of longitudinal studies need to focus on specific hypotheses driven by plausible biological mechanisms for fetal programming and follow children for a sufficient period in order to examine the early manifestations of developmental vulnerability. Intervention studies can then be targeted to altering these mechanisms of intergenerational transmission once identified.


Terahertz-bandwidth photonic temporal differentiator based on a silicon-on-isolator directional coupler.
We experimentally demonstrate a terahertz-bandwidth photonic differentiator employing a silicon-on-insulator directional coupler. The integrated waveguide coupler with two identical paralleled strip waveguides achieves a first-order differentiator when full energy coupling is met from one waveguide to another. The integrated waveguide coupler can offer different operation bandwidths by changing the length and gap of the strip waveguides. Due to the large 3 dB bandwidth of the directional coupler, we implement the first differentiator with an operation bandwidth of 1.25 THz. The performance of this photonic differentiator is tested using Gaussian-like pulses with a pulsewidth of 2.8 ps, 4 ps, 6 ps, 8 ps, and 10 ps, respectively. The differentiation processing errors and relative energy efficiency are also discussed. This silicon chip may have potential applications in integrated photonic computing circuits with sub-picosecond pulses.